Previous funding allowed this component to first compile the ontogenic profiles of opioid receptors. By extending from these studies, this component will address the mechanisms underlying the ontogenesis of kappa opioid receptor (KOR). The genetic basis for the expression of KOR has begun to be dissected and identified. It is hypothesized that the expression of KOR during development is tightly controlled by both intrinsic and external factors. The intrinsic factors include specific developmental programs adopted by the KOR gene for each cell type, as well as the signals communicating these cells during the developmental stages. The external factors include diets, endocrine factors and pharmacological agents. Two aims are proposed for this component: a) to identify and characterize intrinsic factors/developmental programs governing KOR expression during developmental stages and b) to determine how extrinsic factors may modulate the ontogenesis of KOR gene. The first aim will continue to identify genetic elements for the control of KOR expression in developing animals and in differentiating neurons and to examine trans-acting factors that affect the expression of KOR. Secondly, the signals communicating KOR-positive neurons with other cells will be examined in a co-culture system. The second aim will identify and characterize extrinsic factors for KOR expression in developmental stages. Previous finding of vitamin A and nitric oxide (NO) as potent agents regulating the expression of KOR provides the basis for this aim. The negative effect of RA on the intronic silencer of the KOR gene, as well as the positive effect of RA on the GC-boxes of this gene promoter will be examined. Secondly, the NO pathway leading to a rapid suppression of KOR expression will be dissected. Thirdly, unknown factors will continued to be searched with the help of transgenic mice and cell line reporters. Ultimately, this component will address both intrinsic, genetic basis and extrinsic environmental factors on the ontogenesis of KOR.